The Rel pathway is one of the best understood signal transduction pathways. In vertebrates, it controls the activity of the immune and inflammatory response genes as well as that of viral genes. In Drosophila, the Rel pathway functions in the innate immune response and in the establishment of dorsal-ventral (DV) polarity in the early embryo. Rel proteins are also implicated in oncogenesis and apoptosis in vertebrates. We have long been studying the function of the Rel protein Dorsal and its cytoplasmic inhibitor, Cactus. Dorsal represents the last step in a morphogenetic pathway, a pathway initiated during early oogenesis. It establishes a ventral signal that is transduced in the early embryo and results in the formation of the Dorsal ventral-to-dorsal nuclear gradient. Once in the nucleus, Dorsal regulates the expression of specific Zygotic genes resulting in the establishment of the DV axis and the subdivision of this axis into discreet domains. Our experiments are aimed at elucidating how the dorsal nuclear gradient is formed and how dorsal function is controlled. During this funding period we have identified four new genes functioning upstream from or in consort with cactus and dorsal. We propose to continue with their characterization and to identify additional genes functioning in the pathway. Because the Rel pathway is highly conserved in flies and humans, it is likely that the genes identified in our work will also function in vertebrates.